1. Field of the Invention
The present invention, in general, relates to the field of iontophoresis. In particular, the present invention relates to a method and apparatus for transdermal iontophoretic delivery of ionic substances by application of pulsed electrical energy having distinctive, complex waveform characteristics. These waveform characteristics are controlled to provide dual-segment, therapeutic pulses which significantly improve the efficiency of such iontophoretic treatment, without substantially increasing skin irritation.
2. Description of the Prior Art
Iontophoresis is a process which involves the transport of ionic substances into body tissue, such as through the skin, by the passage of a direct electric current through an electrolyte solution containing the ionic substance to be administered. Conventional iontophoretic devices typically include a battery and simple current control circuitry coupled to two electrodes, namely the active and indifferent electrodes. The active electrode contains the desired ionic substance to be administered, e.g., a drug in its ionic form having the same charge as the active electrode. The indifferent electrode is typically moistened with saline solution or provided with some other ionic conductive medium. The indifferent electrode serves as a ground electrode to close the electrical circuit through the body.
Iontophoresis offers many advantages to other conventional drug delivery regimens, such as oral administration by pills or intravenous administration by needle injection. In comparison to needle injection, for example, iontophoresis provides a noninvasive procedure with reduced trauma, pain, anxiety and risk of infection. Iontophoresis is well-adapted for local or topical treatment, such that high local concentration of the drug administered can be accomplished with a corresponding reduction of unwanted systemic side effects. Iontophoresis also offers great flexibility as to the rate of drug administration, regardless of whether the desired therapy is local or systemic, since the rate of drug delivery can be controllably varied by miniaturized programmable circuitry which precisely varies the iontophoretic current applied. Iontophoresis has been used, for example, for transdermal delivery of various drugs such as lidocaine hydrochloride, hydrocortisone derivatives, acetic acid, fluoride, penicillin, and dexamethasone sodium phosphate. It has also been used to deliver pilocarpine nitrate as part of a screening procedure for cystic fibrosis.
While the technique of iontophoretic drug delivery has been used clinically in delivering medication to surface tissues for several decades, the need for improving the efficiency of drug delivery and for reducing the risk of skin burns and general tissue irritation often associated with such therapy has limited its expanded use. The interplay of a multitude of chemical, electrical and physiological factors, which are known to influence iontophoretic drug delivery, present a complex background against which solutions to these problems have been made anything but obvious.
Some of these factors which must be managed include, for example: (a) various electrochemical factors, such as the type, molecular size, weight and ionic concentration of the drug, presence of extraneous ions competing with the charged drug molecules, and pH conditions at the interface of the skin and active electrode; (b) various electronic factors associated with active transport of the charged drug, such as the power source voltage, the type and surface area of the electrodes, use of constant or pulsed DC current, pulse width, and frequency; and (c) various physiological considerations peculiar to treatment of skin tissue, such as its permeability and sensitivity to each particular drug type, as well as the electrical properties of skin tissue. Further complexity arises from the fact that many of these factors can vary from patient to patient, and even as to the same patient as a function of specific body location receiving therapy, duration of therapy or therapeutic drug type.
Various approaches have heretofore been taken toward improving upon the management of the electronic-related factors identified above, but limited drug delivery efficiency has been obtained. It is management of these various electronic-related factors, and more particularly, an improved method and apparatus for more effectively accommodating the electrical properties presented by the skin tissue receiving pulsed iontophoretic drug therapy, to which the present invention is directed.
Since the quantity of ions transferred in an iontophoretic application is directly proportional to the current flow and its duration, conventional iontophoretic devices regulate drug dosage delivery by controlling current flow through the electrodes. Iontophoretic devices are disclosed, for example, with various current regulation schemes in the following patents:
______________________________________ Inventor ______________________________________ U.S. Pat. Nos. 3,794,910 Ninke et al. 3,991,755 Vernon et al. 4,019,510 Ellis 4,141,359 Jacobsen et al. 4,149,533 Ishikawa et al. 4,292,968 Ellis 4,301,794 Tapper 4,340,047 Tapper et al. 4,406,658 Lattin et al. 4,725,263 McNichols et al. 4,764,164 Sasaki. 4,808,152 Sibalis Foreign Pat. Nos. EP 0 292 930 A1 Sibalis EP 0 309 093 A1 Masaki ______________________________________
Prior art iontophoresis devices provide either a constant DC or a pulsed DC current to drive the electrodes. Unfortunately, using either mode of operation has required a tradeoff between drug delivery efficiency and irritation to the skin being treated. Over the same period of operation and peak current amplitude, for example, the constant DC mode will deliver greater quantities of drug than the pulsed DC mode, primarily due to the constant DC mode's uninterrupted current flow (i.e., the effective duration of current flow, or the effective average current, is greater). Associated with the constant DC mode, however, there is a constant polarizing current producing a residual charge within the body tissue, which is at least partially depolarized when operating in the pulsed DC mode during the "off" time interval between pulses. Consequently, the constant DC mode tends to produce greater irritation to the skin beneath the electrode than that caused when using the pulsed DC mode.
Thus, a primary challenge to those skilled in this art over recent years has been to develop techniques for improving the drug delivery efficiency of the pulsed iontophoretic modality without compromising its desirably low skin irritation benefits.
The approaches which the prior art has taken toward further reducing skin irritation and improving the drug delivery efficiency of devices which operate in the pulsed DC mode relate to methods for reducing the residual charge within the body tissue by actively assisting the depolarization function in between therapeutic pulses. U.S. Pat. Nos. 4,301,794 (Tapper) and 4,340,047 (Tapper et al.), for example, teach periodically interrupting a unidirectional treatment current (FIG. 1, treatment current 14 of waveform 12) with a relatively short pulse of current in the opposite direction (pulse 16). U.S. Pat. No. 4,764,164 (Sasaki) also discusses the use of forced-discharge type reverse pulses between therapeutic pulses, as well as the use of a switch mechanism (e.g., FIG. 3, switch 7) coupled in parallel to the skin electrodes to affect depolarization by short-circuit discharge between therapeutic pulses.
Even with these approaches, however, the drug delivery efficiency of iontophoretic devices operating in the pulsed DC mode has not been entirely adequate and a need for significant improvement has continued. As will become apparent from the following, the present invention satisfies that need.